title: TRPA1 and sympathetic activation contribute to increased risk of triggered cardiac arrhythmias in hypertensive rats exposed to diesel exhaust.
abstract: BACKGROUND
  Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias.
  
  
  OBJECTIVE
  We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia.
  
  
  METHODS
  Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 μg/m³ (high) or 150 μg/m³ (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored.
  
  
  RESULTS
  Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE-exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia.
  
  
  CONCLUSIONS
  These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.
authors.affiliation: Environmental Public Health Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. hazari.mehdi@epa.gov
authors.forename: Mehdi S
authors.initials: MS
authors.lastname: Hazari
authors.forename: Najwa
authors.initials: N
authors.lastname: Haykal-Coates
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Winsett
authors.forename: Q Todd
authors.initials: QT
authors.lastname: Krantz
authors.forename: Charly
authors.initials: C
authors.lastname: King
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
authors.forename: Aimen K
authors.initials: AK
authors.lastname: Farraj
mesh_terms: D000157:Aconitine / Q000494:pharmacology*; D000393:Air Pollutants / Q000032:analysis / Q000633:toxicity; D000818:Animals; D017487:Ankyrins / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D015220:Calcium Channels / Q000494:pharmacology*; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D013686:Telemetry; D001335:Vehicle Emissions / Q000032:analysis / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D017487:Ankyrins; D015220:Calcium Channels; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D001335:Vehicle Emissions; D000157:Aconitine